Proteins homologous to the carboxyl terminus of the β and γ chains (fibrinogen-related domain or FRED2) of fibrinogen, including angiopoietins, ficolins and tenascins, have been classified into the fibrinogen-related protein superfamily and have been demonstrated to exert multifaceted roles in immune responses (1-3). For example, fibrinogen can act as a “bridge” between αmβ2-bearing leukocytes to ICAM-1 on endothelial cells, and the engagement of αmβ2 by fibrinogen triggers a series of intracellular signaling events and cellular responses including cytokine secretion and nuclear factor-κB activation (4, 5). Angiopoietin-1 inhibits endothelial cell permeability in response to thrombin and vascular endothelial growth factor in vitro via the regulation of the junctional complexes, PECAM-1 and vascular endothelial cadherin (6). Two independent studies have reported that soluble tenascin blocks T cell activation induced by soluble antigens, alloantigens, or the mitogen Con A (7, 8).
Fgl2, also known as fibroleukin, has been demonstrated to be involved in the pathogenesis of diseases including viral-induced fulminant hepatitis and Th1 cytokine-induced fetal loss syndrome, in which fibrin deposition is a prominent feature (9-11). The gene fgl2 was originally cloned from CTL and the encoded protein shares a 36% homology to the fibrinogen β and γ chains and a 40% homology to the FRED of tenascin (1, 12). The coagulation activity of fgl2 was first described in a murine fulminant hepatitis model (13, 14) and fgl2 prothrombinase was detected in activated reticuloendothelial cells (macrophages and endothelial cells) (9, 15, 16). Fgl2 functions as an immune coagulant with the ability to generate thrombin directly, and thus, fgl2 appears to play an important role in innate immunity.
Human fgl2/fibroleukin expressed by peripheral blood CD4+ and CD8+ T-cells has been shown to be a secreted protein devoid of coagulation activity (17, 18). However, the function for soluble fgl2 protein generated by T-cells has herebefore remained undefined.